Identifying Autophagy-related Genes As Potential Targets for Immunotherapy in Tuberculosis

Purpose: Identifying of host-directed targets and molecular markers of immune response for tuberculosis (TB) immunotherapy is urgent and meaningful. Previous studies have demonstrated an important role of autophagy in the course and pathophysiology of TB and is associated with the efficacy of TB treatment. However, its role in TB immunotherapy is still incomplete.

Methods: The effect of autophagy on intracellular bacteria load was examined in sulforaphane (SFN)-treated THP-1 cells. The immune infiltration was assessed based on public databases. Functional enrichment analysis revealed the pathways involved. LASSO Cox regression analysis was employed to identify hub genes. Moreover, machine learning analysis was used to obtain important targets of TB immunotherapy. Finally, the relationship between hub genes and immune infiltration was assessed, as well as the relevance of chemokines.

Results: We found that SFN reduced intracellular bacteria load by enhancing autophagy in THP-1 cells. Thirty-two autophagy-related genes (ARGs) were identified, three types of immune cells (macrophages, neutrophils, and DC cells) were significantly enriched in TB patients, and 6 hub genes (RAB5A, SQSTM1, MYC, MAPK8, MAPK3, and FOXO1) were closely related to TB immune infiltration. The 32 ARGs were mainly involved in autophagy, apoptosis, and tuberculosis pathways. FOXO1, SQSTM1, and RAB5A were identified as important target genes according to the ranking of variable importance, with FOXO1 being a potential autophagy-related target of TB immunotherapy.

Conclusion: This study highlights the association between autophagy-related genes and immune infiltration in TB. Three key genes, especially FOXO1, regulated by SFN, will provide new insights into diagnostic and immunotherapy strategies for clinical tuberculosis.